It is generally accepted that cigarette smoke is the most important risk factor for COPD, One possibility is the oxidant/antioxidant theory, which proposes that oxidative stress initiates the onset of COPD whereas some antioxidants such as microsomal epoxide hydrolase (mEPHX) and paraoxonase (PON1) play a protective role in the lung, mEPHX is an enzyme involved in the metabolism of smoking induced highly reactive epoxide intermediates. An exon 3 thymine (T) to cytosine (C) mutation changes tyrosine amino acid at 113 residue to histidine, and the enzyme activity is reduced by ≥ 50% (slow phenotype), Aim of work: evaluate the role of serum PON1 activity and genetic polymorphism of mEPHX in the pathogenesis of COPD as to verify the role of oxidant/antioxidant theory in COPD development. PON1 activity assay was done by spectrophotometeric method, an mEPHX gene polymorphism was done using PCR-RFLP. The results showed that there was statistically significant increase in the mutant genotype of mEPHX in COPD than smoker and nonsmoker (P=0.013), HDL-c was showed statistically significant decrease in COPD than smoker and nonsmoker (P=0.001), PON1 was statistically decreased in COPD than smoker and nonsmoker (P=0.015), FEV1/FVC was statistically decreased in COPD than smokers. There was positive correlation between HDL-c and PON1 (r=0.777,p=0.000), FEV1/FVC and PON1 (r=0.54,p=0.000). Conclusion: there was a role for cigarette smoking in the development of COPD, antioxidants were consumed in metabolizing oxidants, mutant mEPHX gene is associated with COPD.